Medical Policy

 

Subject: Rilonacept (Arcalyst®)
Document #: DRUG.00073 Publish Date:    06/28/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the indications for rilonacept (Arcalyst, Regeneron Pharmaceuticals, Inc., Tarrytown, NY), an interleukin-1 (IL-1) inhibitor drug used in the treatment of cryopyrin-associated periodic syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS).

Note: Please see the following document for information concerning another drug that may be used for the treatment of CAPS:

Note: For additional information on review of clinically equivalent cost effective criteria for products addressed in DRUG.00073, please refer to CG-ADMIN-02 Clinically Equivalent Cost Effective Services - Targeted Immune Modulators.

Position Statement

Medically Necessary:

Rilonacept is considered medically necessary for the treatment of individuals 12 years of age and older with either of the following cryopyrin-associated periodic syndromes (CAPS):

  1. Familial cold autoinflammatory syndromes (FCAS); or
  2. Muckle-Wells syndrome (MWS).

Not Medically Necessary:

Rilonacept is considered not medically necessary for an individual with any of the following:

  1. Use of rilonacept in combination with other interleukin-1 inhibitors; or
  2. Use in combination with tumor necrosis factor (TNF) inhibitors; or
  3. Receiving live vaccines; or
  4. Exhibiting evidence of active or chronic infection(s), including tuberculosis, or a history of recurrent infections; or
  5. Has not had a tuberculin skin test (TST) or Centers for Disease Control and Prevention (CDC)-recommended equivalent to evaluate for latent tuberculosis prior to initiating treatment with rilonacept.

Investigational and Not Medically Necessary:

Rilonacept is considered investigational and not medically necessary when the criteria are not met and for all other indications, including but not limited to:

Rationale

Cryopyrin-associated Periodic Syndromes (CAPS)

Rilonacept is an interleukin-1 blocker that is approved by the FDA for the treatment of CAPS, including FCAS and MWS in individuals, age 12 years and older. Interleukin-1 (IL-1) is a signaling protein that acts as a messenger to regulate inflammatory responses; in excess, IL-1 causes clinical signs and symptoms of inflammation. Markers of inflammatory activity, such as C-reactive protein (CRP) and serum amyloid A (SAA), are usually elevated in individuals with CAPS disorders. Rilonacept blocks IL-1β by acting as a decoy receptor that binds IL-1β, and inhibits interaction with cell surface receptors. In addition, rilonacept binds IL-1α and IL-1 receptor antagonist (IL-1ra) with less affinity (Arcalyst Product Information [PI], 2016).

The FDA approval was based on safety and efficacy data from two pivotal trials; however, the FDA approval did not include rilonacept for another CAPS disorder, neonatal-onset multi-systemic inflammatory disease (NOMID), also referred to as chronic infantile neurological cutaneous articular syndrome (CINCA) (Arcalyst PI, 2016). In addition, the FDA approval did not include rilonacept for the treatment of gout flares.

Pivotal phase II trial data demonstrated favorable outcomes for rilonacept for two forms of CAPS in individuals older than 12 years of age. This open-label pilot study (n=5) evaluated the safety and efficacy of rilonacept in individuals with mutation-positive FCAS (Goldbach-Mansky, 2008). At baseline, participants had not previously received treatment with disease modifying anti-rheumatic drugs (DMARDs), prednisone, or IL-1 inhibitors. Primary outcome measures included changes in the level of inflammatory markers, including erythrocyte sedimentation rate (ESR), CRP, and SAA, as well as clinical daily diary scores, where participants recorded signs and symptoms of their disease. Secondary outcomes included the occurrence of flare and amount of time to experience a flare after the initial dose of rilonacept. Other secondary outcomes include safety assessment sand various quality of life (QOL) measures.

Study results demonstrated that all participants experienced significant improvement in daily clinical symptoms of the disease when compared with baseline values (81% mean symptom reduction; p<0.05). Significant improvements were also reported for ESR (58% mean reduction; p<0.01), CRP (88% mean reduction; p<0.001), and SAA (95% mean reduction; p<0.001). The greatest improvement in clinical and laboratory data was observed at day 10 (4 participants) and day 6 (1 participant). QOL measures, using visual analog scale (VAS) measures of physician and patient global assessments, were significantly improved compared with baseline values. During an extension phase of the pilot study, all participants completed 24 months of follow-up while on a dose of 160 milligrams (mg) per week or higher. Results showed that at high doses, participants experienced significant improvements in ESR (p<0.05), but not CRP or SAA. Overall, treatment with rilonacept did not result in serious adverse events (AEs), and all AEs were considered mild or moderate. One participant discontinued treatment due to pain in a finger joint, but this adverse event was considered unrelated to rilonacept.

Hoffman and colleagues (2008) conducted a randomized controlled trial (n=47) to evaluate the safety and efficacy of rilonacept in individuals who were at least 18 years of age with CAPS disorders, had confirmed disease mutation, and typical signs and symptoms observed with FCAS or MWS. Enrollees were evaluated in two separate, sequential studies. Study 1 was a randomized, placebo-controlled trial that evaluated the safety, efficacy, and tolerability of rilonacept compared with placebo. Individuals with active FCAS or MWS were randomized into the treatment group to receive a loading dose of 320 mg of rilonacept or placebo (administered by clinical staff), followed by weekly subcutaneous injections of 160 mg rilonacept or placebo (administered by the participant). Individuals who completed Study 1 were then entered into Study 2, which was comprised of two different parts (Part A and Part B). Part A involved 9 weeks of single-blind treatment with rilonacept (160 mg), followed by Part B, which involved 9 weeks double-blind treatment with rilonacept (160 mg) or placebo. Individuals who completed Study 2 were offered the option to enter a subsequent rilonacept extension study.

Primary outcome measures included the assessment of disease activity. Disease activity was evaluated with the Daily Health Assessment Form (DHAF) (change in the mean symptom score), in which participants rated the severity of symptoms associated with the disease during the previous 24-hour period. Participants also underwent global assessment of disease activity. In addition, physician-provided global assessments were completed, levels of CRP and SAA were measured, and AEs associated with rilonacept were evaluated.

In Study 1, final results demonstrated that rilonacept was significantly better than placebo in the change from baseline for the composite mean symptom score (84% treatment vs. 13% placebo; p<0.0001). In addition, treatment with rilonacept resulted in significant improvements compared with placebo controls for numbers of flare days (p<0.0001), and the mean score for each of five key symptoms (p=0.0001). Compared with placebo, rilonacept treatment resulted in significantly improved physician and participant global assessment of disease activity (p<0.0001 for both measures), and significantly decreased levels of inflammatory disease markers (CRP, p<0.0001; SAA, p=0.006). In Study 2, Part A, participants experienced sustained treatment benefits observed in Study 1. In Study 2, Part B, rilonacept was significantly better than placebo in sustaining relevant symptom scores (mean values) that were achieved during Study 1 (p=0.0002). In addition, participants on rilonacept treatment continued to have reduced number of flare days (both single- and multiple symptoms). Rilonacept was also significantly better than placebo in sustaining improvements in the physician (p<0.0001) and participant (p<0.0001) global assessments of disease activity, and maintaining low levels of disease markers, CRP (p<0.0001) and SAA (p=0.006). In addition, participants experienced significantly fewer limitations with regard to their daily living activities (p=0.006). Study findings suggest that rilonacept results in significant treatment effects compared with placebo in individuals with CAPS.

A total of 74% of individuals receiving rilonacept in Study 1 experienced an adverse event compared with 54% of those receiving placebo (no p-values reported). In Study 1, the most commonly observed AEs included reactions occurring at the injection site (rilonacept, 48%; placebo, 13%) and upper respiratory tract (URI) infections (rilonacept, 26%; placebo, 4%). Similarly, in Study 2, the most common AEs were reactions occurring at the injection site (rilonacept, 36%; placebo, 13%) and headache (rilonacept, 14%; placebo, 0%). A total of six AEs were reported by study participants (n=4). These events included Mycobacterium intracellulare infection, gastrointestinal bleeding and colitis, sinusitis and bronchitis, and Streptococcus pneumoniae meningitis.

The long-term efficacy, safety, and tolerability of rilonacept for improvement in CAPS symptoms are reported in a 72-week open-label extension trial (Hoffman, 2012) that followed the two sequential placebo-controlled phase III studies (Hoffman, 2008; Study 1 and Study 2). Participants (n=57) received weekly subcutaneous rilonacept 160 mg (adults) or subcutaneous rilonacept 2.2 mg/kg, up to 160 mg/week (children). Safety was evaluated in all participants and efficacy was evaluated using a validated composite key symptom score in 56 participants. The long-term treatment with rilonacept up to 96 weeks resulted in improvements in clinical signs and symptoms of CAPS and normalized biomarkers of inflammation with a generally favorable safety and tolerability profile throughout the extended treatment period.

To date, rilonacept has not been evaluated in comparative trials to other IL-1 blocking agents, including anakinra and canakinumab.

Off-FDA Label and Other Proposed Uses of Rilonacept

Prevention of Gout Flares During Urate Lowering Therapy

There is a lack of evidence in the peer-reviewed published literature regarding a treatment benefit of rilonacept compared with standard therapies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, and colchicine, for the prevention of gout flares during urate lowering therapy (ULT).

Schumacher and colleagues (2012) evaluated the efficacy and safety of rilonacept for prevention of gout flares during initiation of ULT in a randomized, double-blind, placebo-controlled study of 241 adults with ≥ two gout flares (within the past year) and a serum urate level ≥ 7.5 mg/dl. Participants who were initiated on allopurinol 300 mg daily were randomized to receive 16 once-weekly subcutaneous injections of placebo, rilonacept 80 mg, or rilonacept 160 mg. Allopurinol was titrated to achieve a serum urate level of < 6.0 mg/dl. The primary efficacy endpoint was the number of gout flares per participant through week 16. More participants in the rilonacept groups (80.0% in the 80 mg and 86.4% in the 160 mg rilonacept groups) completed the study than in the placebo group (72.5%; p<0.05 for the rilonacept 160 mg group vs. the placebo group). Over 16 weeks, the mean number of gout flares per participant was significantly reduced with rilonacept treatment. Significantly lower proportions of participants reported ≥ one gout flares with rilonacept 80 mg (18.8%) and rilonacept 160 mg (16.3%) compared with placebo (46.8%; p<0.001 for both). The efficacy profile suggests that rilonacept may have the potential to improve long-term disease control for some individuals by reducing flares during the first months after ULT initiation. The most frequently reported AEs were injection site reactions, upper respiratory tract infection, and headache, similar among treatment groups. A potential limitation of this study is that the starting dose of allopurinol (300 mg daily in participants with normal renal function) may increase the flare risk relative to a lower starting dose.

Mithra and colleagues (2013) evaluated the efficacy and safety of rilonacept for gout flare prevention during initiation of ULT with allopurinol in an international phase III, randomized placebo-controlled trial (PRESURGE-2) of 248 adults (ages 18-79 years) from South Africa (75% of participants), Germany, and Asia. Participants with gout who experienced two or more gout flares within the past year were randomized to once-weekly subcutaneous treatment with placebo (n=82), rilonacept 80 mg (n=82), or rilonacept 160 mg (n=84) for 16 weeks. Although anti-inflammatory agents such as colchicine and NSAIDs were not allowed for flare prevention, the investigators treated acute gout flares for up to 10 days with an NSAID and/or oral glucocorticoid while study treatments were continued. The primary endpoint was the number of gout flares through week 16; a safety follow-up was performed 5 weeks after the last injection of the study drug. For the 222 (90%) participants who attended the week 16 visit, the rilonacept 160 mg group reported significantly fewer gout flares per participant (0.34, 95% confidence interval [CI], 0.15, 0.52) relative to placebo (1.23, 95% CI, 0.89, 1.58; p<0.0001), a 72.6% rate reduction. Sequential testing of the rilonacept 80 mg dose showed significantly fewer gout flares per participant 0.35, 95% CI, 0.21, 0.50; p<0.0001), a 71.3% rate reduction. The overall incidence of treatment-related AEs (as considered by a study investigator) was 7 (8.5%), 26 (31.7%), and 21 (25%) in the placebo, rilonacept 80 mg, and rilonacept 160 mg groups, respectively. The most common AEs included injection site reactions, upper respiratory tract infection, influenza viral infections, and headache. Serious AEs occurred in 5 (6.1%; including appendicitis and pyelonephritis) and 3 (3.6%) participants in the rilonacept 80 mg and rilonacept 160 mg groups, respectively. Limitations of this study include an evaluation of participants that were predominately male (n=231, 93%) and a short primary outcome endpoint measured through 16 weeks. In addition, the investigators stated that "across treatment groups, similar doses of allopurinol resulted in similar reductions in uric acid levels, indicating that rilonacept did not appear to alter the ability of allopurinol to reduce uric acid."

Sundy and colleagues (2014) evaluated the use of rilonacept for gout flare prevention in individuals receiving ULT in a phase III, international safety (RESURGE) study. A total of 1315 adults, ages 18-80 years with gout who were initiating or continuing ULT, were randomized to treatment with weekly subcutaneous injections of rilonacept 160 mg or placebo for 16 weeks followed by a 4-week safety follow-up. The primary endpoint was safety as assessed by AEs and laboratory values. A total of 66.6% of participants in the rilonacept group versus 59.1% in the placebo group had ≥ one AEs, with slightly more AE-related withdrawals with rilonacept (4.7% vs. 3.0%); however, this was attributed to a greater incidence of injection site reactions in the rilonacept group (15.2% rilonacept vs. 3.3% placebo). Serious AEs were similar in both groups, including serious infections (0.9% placebo; 0.5% rilonacept). The most common AEs were reported as headache, arthralgia, injection site erythema, accidental overdose, and pain in extremity. Rilonacept resulted in 70.3% fewer gout flares per participant (p<0.0001), fewer participants with ≥ one and ≥ two gout flares (p<0.0001), and 64.9% fewer gout flare days (p<0.0001) relative to placebo at 16 weeks of treatment. The authors concluded the safety profile of rilonacept was consistent with previous studies.

Khanna and colleagues (2014) performed a systematic review of the peer-reviewed published literature and Cochrane database on pharmacologic and non-pharmacologic agents used for the treatment of acute gout attacks. The evaluable randomized controlled trials included use of NSAIDs, corticosteroids, colchicine, adrenocorticotropic hormone (ACTH), IL-1 inhibitors, topical ice, or herbal supplements. The authors concluded that "rilonacept was demonstrated to be not as effective" as other agents for treatment of acute gout attacks.

Sivera and colleagues (2014) performed a meta-analysis to assess the benefits and harms of IL-1 inhibitors (anakinra, canakinumab, rilonacept) for acute gout flares. The reviewers identified one study (Terkeltaub, 2013) that compared rilonacept with indomethacin for the treatment of acute gout flares. The mean change (improvement) in pain from baseline with indomethacin was 4.3 points (measured on a 0 to 10 numerical rating scale, where 0 was no pain); pain was improved by a mean of only 2.5 points with rilonacept (95%CI, 0.29 to 4.75, 25% less improvement in absolute pain with rilonacept). The study did not measure outcomes such as inflammation, functional health-related quality of life or participant global assessment of treatment success. AEs were reported in 27 of 75 (36%) participants in the rilonacept group and 23 of 76 (30%) in the indomethacin group. Based on this low-quality evidence, the authors concluded that rilonacept alone or in combination with indomethacin did not provide any additional pain relief at 72 hours compared to indomethacin alone in the treatment of acute gout flares.

The American College of Rheumatology (ACR) guidelines for management of gout state that the role of IL-1 inhibitors for the off-label treatment of acute gout is uncertain (Khanna, 2012).

On July 30, 2012, the FDA issued a "Complete Response" letter to Regeneron Pharmaceuticals, Inc. following the manufacturer's submission of rilonacept (subcutaneous) for prevention of gout flares in individuals initiating ULT. The FDA requested additional clinical data, including chemistry, manufacturing and controls information before giving further consideration of approval of rilonacept for this indication. The FDA request was based in part on the rate of serious treatment-related AEs (including 6 rilonacept-treated participants who developed malignancies) reported during the clinical trials and whether the limited duration of rilonacept treatment was sufficient to prevent gout flares (that is, 16 weeks). At this time, the FDA has not approved the use of rilonacept for any gout-related condition, including prevention of gout flares during ULT or the treatment of gouty arthritis.

Systemic Juvenile Idiopathic Arthritis (SJIA)

Two published studies have evaluated the safety and efficacy of rilonacept for the treatment of SJIA. Ilowite and colleagues (2014) conducted a 4-week randomized, double-blind, placebo-controlled trial that was incorporated into a 24-week randomized multicenter design, followed by an open-label phase. A total of 71 children who had active arthritis in ≥ two joints were randomized (1:1) to two study groups. Participants in the rilonacept arm received a subcutaneous loading dose of 4.4 mg/kg followed by 2.2 mg/kg weekly beginning on day 0. Participants in the placebo arm received placebo for 4 weeks followed by a loading dose of rilonacept at week 4 followed by weekly maintenance doses. The primary endpoint was time to response using the adapted ACR Pediatric 30 criteria, absence of fever, and taper of the dosage of systemic corticosteroids. The time to response was shorter in the rilonacept arm than in the placebo arm (p=0.007). The secondary analysis showed that 20 (57%) of 35 participants in the rilonacept arm had a response at week 4 compared with 9 (27%) of 33 participants in the placebo arm (p=0.016). AEs were similar in the two study arms.

Lovell and colleagues (2013) evaluated the long-term safety and efficacy of rilonacept in individuals with SJIA (ages 4-20 years) during 23 months of open-label treatment (three phases) after the 4-week, double-blind, placebo-controlled phase. The efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted ACR Pediatric 30, 50, and 70 response criteria, respectively. Reductions in the median daily dose of oral prednisone were evaluated in addition to improvements in laboratory parameters of disease activity. A total of 24 participants entered the double-blind study and 23 entered the open-label period. At week 4 during the double-blind phase, no significant differences in efficacy were observed between the rilonacept- and placebo-treated participants; however, fever and rash completely resolved by month 3 in all participants during the open-label treatment period. The adapted ACR Pediatric 30, 50, and 70 response rates at 3 months (from the start of the study) were 78.3%, 60.9%, and 34.8%, respectively, and generally maintained over the study duration. Prednisone doses were decreased or prednisone therapy discontinued in 22 of 23 participants. No deaths, malignancies, or serious or opportunistic treatment-related infections were reported. A total of 3 participants withdrew from the study due to AEs during long-term therapy (3 total, 1 each for depression, injection-site reactions, and pulmonary fibrosis/macrophage activation syndrome which was assessed as not related to the study drug). Although there were improvements in some clinical parameters, the primary efficacy endpoint, assessment of differences in the adapted ACR Pediatric 30 response rate in rilonacept-treated participants compared to placebo-treated participants, was not achieved during the 4-week double-blind phase.

The 2013 ACR recommendations for the treatment of juvenile idiopathic arthritis do not recommend the use of rilonacept as first-line treatment of children with JIA. Use of rilonacept as a second-line treatment is uncertain in this same population (Ringold, 2013). At this time, the FDA has not approved rilonacept for the treatment of SJIA.

Summary of Other Proposed Uses for Rilonacept

Familial Mediterranean Fever (FMF)

Rilonacept has been studied for use in the treatment of other rare conditions. Hashkes and colleagues (2012) evaluated the use of rilonacept in a randomized, double-blind, single-participant alternating treatment study and health-related quality of life study (Hashkes, 2014) in 14 individuals with poorly controlled FMF that was resistant to, or intolerant of colchicine. A total of 12 participants completed two or more treatment courses. The median number of attacks per month was 0.77 with rilonacept versus 2.00 with placebo (median difference, -1.74; 95% CI, -3.4 to -0.1; p=0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; p=0.004) and with a decrease in attacks of > 50% compared with the baseline rate during screening (75% vs. 35%; p=0.006) than with placebo; however, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days; p=0.32). Limitations of this trial include the small sample size and the heterogeneity of participants (including age, FMF mutations, and colchicine resistance or intolerance).

In a Cochrane review, Wu and colleagues (2015) reported there are limited randomized controlled studies assessing interventions for people with FMF. Based on the evidence (Hashkes, 2014), there was no significant reduction in the number of participants experiencing attacks at 3 months when rilonacept was used in individuals who were colchicine-resistant or colchicine-intolerant. The authors recommended conducting further randomized controlled studies to evaluate the use of rilonacept and colchicine before a comprehensive conclusion can be drawn regarding the efficacy and safety of these drugs for reducing inflammation in FMF.

Schnitzler Syndrome

Krause and colleagues (2012) conducted a prospective, single-center, open-label study of 8 individuals with Schnitzler syndrome. After a 3-week baseline, participants received a subcutaneous loading dose of rilonacept 320 mg followed by weekly subcutaneous doses of 160 mg for up to 1 year. The primary efficacy outcome was determined by participant-based daily health assessment forms, physician's global assessment (PGA), and measurement of inflammatory markers including CRP and SAA. Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment and PGA scores compared with baseline levels (p<0.05). Additional study is needed in a larger randomized population of individuals to determine the net health benefit of rilonacept for the treatment of Schnitzler syndrome.

NOMID

Rilonacept has been proposed for use in a rare type of CAPS disorder called NOMID. The off-label recommendation is based on the beneficial treatment effects observed in the clinical studies of rilonacept for other CAPS disorders (FCAS and MWS); however, there is a lack of peer-reviewed published case series or clinical trials reporting a treatment effect of rilonacept for this condition.

Subacromial Bursitis

Carroll and colleagues (2015) compared rilonacept with triamcinolone acetonide in a randomized, non-inferiority, single-center, unblinded study of 33 individuals with subacromial bursitis. A total of 20 participants received 160 mg intra-bursal injection of rilonacept and 13 received a 6 milliliter mixture of lidocaine, bupivacaine, and 80 mg triamcinolone acetonide. Outcomes measurements were recorded at time of injection, 2 days later, and 2 and 4 weeks after injection. The primary outcome was improvement in QuickDASH 4 weeks post-injection. Both treatment groups demonstrated a statistically significant improvement in QuickDASH 4 weeks post-injection, but triamcinolone acetonide injection offered greater improvement over rilonacept injection (p=0.004). Both treatment groups demonstrated improvement in subject-reported pain; however, between group comparison at 4 weeks showed that triamcinolone injection was superior to rilonacept injection (p=0.044). No statistically significant differences in adverse events were noted between groups, but subjects who received rilonacept experienced more episodes of diarrhea and headache. The authors concluded that while improvement in QuickDASH and pain was noted with a single intra-bursal injection of rilonacept at 4 weeks, injection with triamcinolone acetonide was more effective and resulted in less adverse events. Additional well-designed studies are needed to determine the effectiveness of rilonacept in treating subacromial bursitis and if it is superior to injections of conventional agents.

Other Conditions

A search of the ClinicalTrials.gov database has identified studies in various phases evaluating rilonacept for other conditions including, but not limited to, cold contact urticaria, deficiency of the interleukin-1 receptor antagonist (DIRA) disease, systemic sclerosis (scleroderma), and inflammation in cardiovascular and chronic kidney disease (CKD). At this time, the FDA has not approved rilonacept for the treatment of any of these conditions.

Background/Overview

Description of the Conditions

Cryopyrin-associated Periodic Syndromes (CAPS)

CAPS refers to a group of rare autoinflammatory disorders ("cyropyrinopathies"), including MWS, FCAS, and NOMID. CAPS are autosomal dominant inherited disorders. These disorders are associated with specific mutations in the cold-induced autoinflammatory syndrome-1 (CIAS1) gene that ultimately result in the excessive release of interleukin-1 (IL-1). Inflammatory symptoms for all disorders generally include fever, rash (similar to urticaria), arthralgia, myalgia, fatigue, and conjunctivitis. NOMID is the most severe of the CAPS disorders and causes fever with inflammation in multiple organs. Newborn babies can have signs of infection (for example, fever and rash) but no infection is found. In MWS, individuals develop episodic fever, rash, red eyes, joint pain and severe headaches with vomiting. Episodes last from 1-3 days. Deafness or partial hearing loss often develops by teenage years. In FCAS, exposure to cold (including air-conditioning) and other environmental triggers causes a hive-like rash. Individuals also can develop fever, chills, nausea, severe thirst, headaches and joint pain. Episodes usually last up to 1 day (ACR, 2015).

Some individuals with CAPS disorders have chronically elevated levels of SAA and CRP. Elevated levels of SAA may be associated with reactive amyloidosis and renal failure, which are more severe complications of CAPS. Although the incidence of amyloidosis is about 2% in those with FCAS, this more serious condition affects 25% of individuals with MWS (Hoffman, 2008; Neven, 2008).

In the United States and Europe, the incidence of CAPS is approximately 1 in 1,000,000 with a prevalence of 300 to 500 individuals. FCAS is more commonly observed in the United States, and MWS is more common in Europe. Men and women are both affected by the disease, and all ethnic groups are reported to be susceptible (ACR, 2015; Neven, 2008).

In the past, individuals have been treated with NSAIDs, steroids, or methotrexate to reduce symptoms of inflammation associated with CAPS. However, newer drug therapies that target IL-1 have been shown to be safe and effective for treating CAPS disorders. These include rilonacept (Arcalyst), anakinra (Kineret® , Amgen, Thousand Oaks, CA), and canakinumab (Ilaris, Novartis Pharma Stein AG, East Hanover, NJ). Other supportive treatment approaches include physical therapy, splints, and other physical aids or tools to treat and support joint deformities, when necessary (ACR, 2015). Treatment for CAPS must be maintained throughout life since there is no known cure.

Familiar Mediterranean Fever (FMF)

FMF is a genetic disease resulting in recurrent attacks of fever, abdominal pain, chest pain, arthritis and rash. Pyrin, the protein that has a defect in FMF has an important role in the regulation of a molecule called interleukin (IL)-1 beta production and activity, has an important role in the process of inflammation in FMF. Approximately 5% to 15% of individuals with FMF continue to have attacks despite treatment with colchicine.

Gout Flares and Gouty Arthritis

Gout is a monosodium urate monohydrate crystal-induced form of arthritis and is the most common rheumatic disease of adults. The condition and its complications affect more than 3 million Americans and occur more often in men over the age of 30, women after menopause, and in individuals with kidney disease. According to the ACR guidelines for the management of gout (Khanna, 2012), the prevalence of gout in the United States has risen over the last few decades, "…mediated by factors such as an increased prevalence of comorbidities that promote hyperuricemia, including hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus, and chronic kidney disease (CKD)."

Gout occurs when excess uric acid, a normal waste product in the blood, deposits needle‐like urate crystals in and around the joints. These crystals can attract white blood cells, leading to severe, painful gout attacks and chronic arthropathy (that is, gouty arthritis/gout flares). Uric acid also can deposit in the urinary tract causing kidney stones. Certain foods, such as shellfish and red meats, alcohol in excess, and food and drinks high in sugar (fructose), in addition to some medications, such as low-dose aspirin, certain diuretics (for example, hydrochlorothiazide), and immunosuppressants used in organ transplants (for example, cyclosporine and tacrolimus) may raise uric acid levels and lead to attacks of gout (gout flares).

Systemic Juvenile Idiopathic Arthritis (SJIA)

SJIA is a rare, disabling, and potentially life-threatening form of childhood arthritis that causes severe inflammation throughout the body. The cause of the disease is unknown. SJIA affects 5 to 15 children per 100,000 in the U.S. and is considered the most severe subtype of JIA. SJIA is distinguished from other forms of JIA by the features including spiking fevers, rash, swelling and inflammation of lymph nodes, liver, and spleen, and high white blood cell and platelet counts. Arthritis may persist even after the fevers and other symptoms have disappeared. Up to 30% of children will still have active disease after 10 years. Secondary medical complications include amyloidosis, joint deformities with loss of function, growth failure, osteoporosis, and developmental delay.

Definitions

Amyloidosis: A rare disease that occurs when amyloids, abnormal proteins, are produced in the bone marrow, and can be deposited in any tissue or organ. Amyloidosis affects the heart, kidneys, liver, spleen, nervous system, and the digestive tract. Severe amyloidosis can lead to life-threatening organ failure. 

Arthralgia: Joint pain, which may be a symptom of injury, infection, or illness.

Autoimmune disease: Diseases which arise from disorders in the adaptive (humoral) immune system.  The adaptive immune system consists of specialized B and T cells which only recognize a specific antigen.  In autoimmune diseases, the B and T cells of the adaptive immune system lose the ability to differentiate self from non-self.

Autoinflammatory disease: Rare disorders (often the result of genetic mutation) that cause systemic inflammation due to problems in the innate immune system (neutrophils, macrophages, natural killer cells, which are the first immune cells to respond to an infection).

Autosomal dominant: If a disease is autosomal dominant, an individual only requires the abnormal gene to be passed from one parent in order for the disease to be inherited.

Conjunctivitis: Inflammation of the conjunctiva, the transparent membrane that lines the eyelid; also known as "pink eye."

Disease modifying anti-rheumatic drugs (DMARDs): A variety of medications which work by altering the immune system function to halt the underlying processes that cause certain forms of inflammatory arthritis including RA, ankylosing spondylitis, and psoriatic arthritis.

Interleukin-1 beta (IL-1ß) antagonist: A class of biologic DMARDs that work by binding human IL-1ß and neutralize its activity by blocking its interaction with IL-1 receptors. A drug in this class includes canakinumab (Ilaris, Novartis Pharma Stein AG, East Hanover, NJ).

Interleukin-1 receptor antagonist (IL-1Ra): A class of biologic DMARDs that inhibits inflammation and pain by blocking pro-inflammatory interleukin-1 cytokine which plays a role in cell destruction. Drugs in this class include anakinra (Kineret), a recombinant form of human IL-1Ra, and rilonacept (Arcalyst).

Myalgia: Muscle pain or ache.

Urticaria: Hives or skin rash characterized by red and raised bumps that may itch, burn, or sting.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS  
J2793 Injection, rilonacept, 1 mg [Arcalyst]
   
ICD-10 Diagnosis    
M04.2 Cryopyrin-associated periodic syndromes [when specified as FCAS or MWS]  

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above for those situations described in the Position Statement as not medically necessary.

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications: 

  1. Carroll MB, Motley SA, Wohlford S, Ramsey BC. Rilonacept in the treatment of subacromial bursitis: a randomized, non-inferiority, unblinded study versus triamcinolone acetonide. Joint Bone Spine. 2015; 82(6):446-450.
  2. Demirkaya E, Erer B, Ozen S, Ben-Chetrit E. Efficacy and safety of treatments in Familial Mediterranean fever: a systematic review. Rheumatol Int. 2016; 36(3):325-331.
  3. Goldbach-Mansky R, Shroff SD, Wilson M, et al. A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum. 2008; 58(8):2432-2442.
  4. Hashkes PJ, Spalding SJ, Giannini EH, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012; 157(8):533-541. Erratum in: Ann Intern Med. 2014; 160(4):291-292.
  5. Hashkes PJ, Spalding SJ, Hajj-Ali R, et al. The effect of rilonacept versus placebo on health-related quality of life in patients with poorly controlled familial Mediterranean fever. Biomed Res Int. 2014; 2014:854842.
  6. Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008; 58(8):2443-2452.
  7. Hoffman HM, Throne ML, Amar NJ, et al. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin Ther. 2012; 34(10):2091-2103.
  8. Ilowite NT, Prather K, Lokhnygina Y, et al. Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2014; 66(9):2570-2579.
  9. Khanna PP, Gladue HS, Singh MK, et al. Treatment of acute gout: a systematic review. Semin Arthritis Rheum. 2014; 44(1):31-38.
  10. Krause K, Weller K, Stefaniak R, et al. Efficacy and safety of the interleukin-1 antagonist rilonacept in Schnitzler syndrome: an open-label study. Allergy. 2012; 67(7):943-950.
  11. Lovell DJ, Giannini EH, Reiff AO, et al. Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. Arthritis Rheum. 2013; 65(9):2486-2496.
  12. Mitha E, Schumacher HR, Fouche L, et al. Rilonacept for gout flare prevention during initiation of uric acid-lowering therapy: results from the PRESURGE-2 international, phase 3, randomized, placebo-controlled trial. Rheumatology (Oxford). 2013; 52(7):1285-1292.
  13. Neven B, Prieur AM, Quartier dit Maire P. Cryopyrinopathies: update on pathogenesis and treatment. Nat Clin Pract Rheumatol. 2008; 4(9):481-489.
  14. Schumacher HR Jr, Evans RR, Saag KG, et al. Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study. Arthritis Care Res (Hoboken). 2012; 64(10):1462-1470.
  15. Sundy JS, Schumacher HR, Kivitz A, et al. Rilonacept for gout flare prevention in patients receiving uric acid-lowering therapy: results of RESURGE, a phase III, international safety study. J Rheumatol. 2014; 41(8):1703-1711.
  16. Terkeltaub RA, Schumacher HR, Carter JD, et al. Rilonacept in the treatment of acute gouty arthritis: a randomized, controlled clinical trial using indomethacin as the active comparator. Arthritis Res Ther. 2013; 15(1):R25.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Rheumatology (ACR). 2015. Cryopyrin-associated autoinflammatory syndromes (CAPS). Available at: http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Cryopyrin-Associated_Autoinflammatory_Syndromes_(CAPS)_(Juvenile)/. Accessed on March 9, 2017.
  2. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part II: therapy and anti-inflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res (Hoboken). 2012; 64(10):1447-1461.
  3. Rilonacept. In: DrugPoints System (electronic). Truven Health Analytics. Greenwood Village, CO. Updated November 14, 2016. Available at: https://www.micromedexsolutions.com . Accessed on March 9, 2017.
  4. Rilonacept [Product Information], Tarrytown, NY. Regeneron Pharmaceuticals, Inc. September 2016. Available at: https://www.regeneron.com/sites/default/files/Arcalyst_FPI.pdf . Accessed on March 9, 2017.
  5. Rilonacept Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio. Lexi-Comp., Inc. February 1, 2011. Accessed on March 9, 2017.
  6. Ringold S, Weiss PF, Beukelman T, et al. 2013 Update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013; 65(10):2499-2512.
  7. Sivera F, Wechalekar MD, Andrés M, et al. Interleukin-1 inhibitors for acute gout. Cochrane Database Syst Rev. 2014;(9):CD009993.
  8. Wu B, Xu T, Li Y, Yin X. Interventions for reducing inflammation in familial Mediterranean fever. Cochrane Database Syst Rev. 2015;(3):CD010893.
Index

Interleukin-1 (IL-1) inhibitor

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  09/27/2017 Added Note to Description section regarding CG-ADMIN-02.
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Updated formatting in Position Statement section. Other format edits to the Rationale. Updated Description, Definitions and References sections. Updated Coding section to remove diagnosis codes not specific to CAPS.
  10/01/2016 Updated Coding section with 10/01/2016 ICD-10-CM diagnosis code changes.
Revised 05/05/2016 MPTAC review. Clarified the NMN criterion for latent tuberculosis testing, adding Prevention to the Centers for Disease Control (CDC) title. Added subacromial bursitis to the INV and NMN statement. Updated Rationale, Background, and References sections. Removed ICD-9 codes from Coding section.
Revised 05/07/2015 MPTAC review. Clarified the not medically necessary statement criteria. Added specific medical conditions to the investigational and not medically statement. Updated Rationale, Background, References, Websites for Additional Information, and Index sections.
New 02/05/2015 MPTAC review. Initial document development.